Process for the preparation of chiral isofluoroenes

ABSTRACT

There is provided a process for the preparation of a chiral insecticidal and acaricidal compound of formula I.  
                 
 
     Also provided are intermediate compounds useful in the process of the present invention.

BACKGROUND OF THE INVENTION

[0001] 1,4-diaryl-2-fluoro-2-butenes and a method for their preparation are described in U.S. Pat. No. 5,998,673. Said compounds are useful as insecticidal and acaricidal agents and for protecting plants from damage caused by insect and acarid attack and infestation. Although U.S. Pat. No. 5,998,673 discloses and claims optical isomers of said 1,4-diaryl-2-fluoro-2-butenes, it does not provide a method for their preparation.

[0002] It is therefore an object of the present invention to provide a process for the preparation of chiral 1,4-diaryl-2-fluoro-2-butenes.

[0003] It is also an object of the present invention to provide intermediates useful in said process.

[0004] These and other objects of the present invention will become more apparent from the detailed description thereof set forth below.

SUMMARY OF THE INVENTION

[0005] There is provided a process for the preparation of a chiral compound of formula I

[0006] wherein

[0007] Ar is phenyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy or hydroxy groups,

[0008] 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C0-C₄alkoxy or C₁-C₄haloalkoxy groups, or

[0009] a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups;

[0010] R is C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl or C₃-C₆halocycloalkyl;

[0011] Ar, is phenoxyphenyl optionally substituted with any combination of from one to six halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0012] phenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0013] biphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0014] phenoxypyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0015] benzylpyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0016] benzylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0017] benzoylphenyl optionally substituted with any combination of from one to five halogen, C0-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0018] 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or

[0019] a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, and

[0020] the (E)- and (Z)-isomers thereof,

[0021] which process comprises the following steps:

[0022] a) treating a racemic ester of formula II

[0023] wherein Ar and R are defined as hereinabove and R₄ is C₁-C₄alkyl with an esterase to form a first mixture of either R-acid IIIa and S-ester IIIb

[0024] or of S-acid IIIc and R-ester IIId

[0025] b) separating said acid IIIa or IIIc from said ester IIIb or IIId;

[0026] c) reducing said acid IIIa or IIIc or said ester IIIb or IIId to obtain a chiral alcohol IV having the R- or S-configuration

[0027] b) reacting said chiral alcohol with an arylsulfonyl halide Ar₂SO₂X

[0028] wherein Ar₂ is phenyl, p-chlorophenyl, or p-tolyl, and

[0029] X is chloro, bromo or fluoro to afford a sulfonate of formula V

[0030] e) reacting said sulfonate V with a cyanide-delivering agent to afford a nitrile of formula VI

[0031] f) hydrolysing said nitrile VI to afford an acid of formula VII

[0032] g) esterifying said acid VII with an alcohol R₁OH, wherein R₁ is C₁-C₄ alkyl to afford an ester of formula VIII

[0033] h) fluorinating said ester to afford a fluoro-ester of formula IX

[0034] i) reacting said fluoro ester with an aldehyde Ar₁CH₂CHO, wherein Ar₁ is defined as hereinabove, in a solvent in the presence of a base to afford a second mixture of 4 chiral diastereomeric hydroxy-esters of formula X

[0035] j) optionally separating said second mixture X into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers;

[0036] k) treating said hydroxy-ester mixture X, Xa or Xb with an acylating agent R₂COX₁, wherein R₂ is C₁-C₄alkyl and

[0037] X₁ is Cl, Br or R₂COO, to afford a fifth mixture of 4 chiral diastereomeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or a seventh mixture of 2 chiral diastereomeric acyloxy esters XIb

[0038] l) optionally separating said sixth or seventh mixture into essentially pure chiral diastereomeric acyloxy esters;

[0039] m) hydrolyzing said pure chiral acyloxy esters or mixtures of esters of formula XI to afford a hydroxy-acid of formula XII

[0040] and

[0041] n) heating said hydroxy-acid XII with an arylsulfonyl halide Ar₃SO₂X₂, wherein Ar₃ is phenyl, p-chlorophenyl, or p-tolyl, and

[0042] X₂ is chloro or bromo to afford the desired chiral compound of formula I.

[0043] The invention further provides chiral intermediate compounds useful in the process of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0044] Although chiral 1,4-diaryl-2-fluoro-2-butenes are described in U.S. Pat. No. 5,998,673, no method for their preparation is disclosed.

[0045] Advantageously, the present invention provides a method for the preparation of chiral compounds of formula I

[0046] wherein Ar, R and Ar₁ are defined as above.

[0047] In accordance with the process of this invention racemic ester II is enzymatically hydrolyzed with an esterase to afford a first mixture of acid IIIa having the R-configuration, and unhydrolyzed ester IIIb, having the S-configuration, which is separated. Said acid IIIa or said ester IIIb is reduced to obtain a chiral alcohol IV having the R- or S-configuration; said alcohol is reacted with an arylsulfonyl halide Ar₂SO₂X to afford a sulfonate of formula V; said sulfonate is treated with a cyanide-delivering agent to afford a nitrile of formula VI; said nitrile is hydrolyzed to yield an acid of formula VII; said acid is esterified with an alcohol R₁OH to yield an ester of formula VIII; said ester is fluorinated to afford a fluoro-ester of formula IX; said fluoro-ester is reacted with an aldehyde Ar₁CH₂CHO in a solvent in the presence of a base to afford a second mixture of 4 chiral diasteromeric hydroxy-esters of formula X; optionally said second mixture can be separated into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers; said hydroxy-ester mixture X, Xa, or Xb is treated with an acylating agent R₂COX, to afford a fifth mixture of 4 chiral diasteromeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or seventh mixture of chiral diasteromeric acyloxy esters XIb; optionally, said sixth or seventh mixture can be separated into essentially pure chiral diastereomeric acyloxy esters; said pure chiral acyloxy esters or mixtures of esters of formula XI are hydrolyzed to a hydroxy acid of formula XII; and finally, said hydroxy acids are heated with an arylsulfonyl halide Ar₃SO₂X₂ to afford the desired chiral compound of formula I. The process is depicted in Flow Diagram I wherein R₄ is depicted as methyl.

[0048] The wavy lines in structural formula I represent either the E isomeric or the Z isomeric configuration about the carbon-carbon double bond.

[0049] Non-polar solvents suitable for use in the process of the invention are essentially water-free solvents such as aromatic hydrocarbons (e.g. toluene, benzene, xylene, naphthalene or the like, preferably toluene), halogenated aromatic hydrocarbones (e.g. chlorobenzene, dichlorobenzene or the like), hydrocarbons (e.g. chloroform, methylene chloride, dichlorethane, or the like, or any of the conventional, preferably water imiscible, organic non-polar solvents.

[0050] Preferred non-polar solvents suitable for use in the process of the invention are hydrocarbons and aromatic hydrocarbons such as hexane, heptane, toluene, ethylbenzene or the like.

[0051] Polar aprotic solvents suitable for use in the inventive process are dimethylformamide, dimethylsulfoxide, tetrahydrofuran, diethyl ether, or the like.

[0052] Preferred polar aprotic solvents suitable for use in the process of the invention are dimethylformamide and dimethylsulfoxide.

[0053] Derivitizing agents suitable for use in the formation of V are triarylphosphine/trialkylphosphines such as triphenylphosphine and triethylphosphine and carbon tetrahalides such as carbon tetrachloride and carbon tetrabromide as well as arylsulfonyl halides such as p-toluene sulfonyl chloride, p-toluene sulfonyl bromide, p-toluene sulfonyl fluoride, benzenesulfonyl bromide, benzenesulfonyl chloride, benzenesulfonyl fluoride, p-chlorobenzenesulfonyl bromide, p-chlorobenzenesulfonyl chloride and p-chlorobenzenesulfonylfluoride or alkylsulfonyl halides such as methane sulfonyl chloride, preferably p-toluene sulfonyl chloride. Suitable bases are resin-bound tertiary organic bases such as polystyrene diisopropyl ethylamine and tertiary organic bases such as triethyl amine and diisopropyl ethyl amine and pyridine, preferably triethlamine. Reaction temperatures may vary from about 0° C. to reflux, preferably from about 25° C. to about 50° C., more preferably about 25° C.

[0054] Cyanide delivering agents suitable for the formation of nitrile VI are metal cyanides, alkali earth metal cyanide and alkali metal cyanide such as potassium cyanide, zinc cyanide and sodium cyanide, preferably sodium cyanide. Reaction temperatures may vary from about 25° C. to about 180° C., preferably from about 50° C. to about 125° C., more preferably about 90° C.

[0055] Suitable agents for the hydrolysis of nitrile VI are aqueous acids such as sulfuric acid or hydrochloric acid in the presence of or without the presence of alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol and t-butyl alcohol, aqueous alkali or alkali earth bases such as potassium hydroxide, calcium hydroxide and sodium hydroxide, preferably sodium hydroxide. Reaction temperatures may vary from about 25° C. to about 100° C., preferably from about 50° C. to about 100° C., more preferably about 100° C.

[0056] Reaction temperatures suitable for the esterification of acid VII vary from about −10° C. to about 40° C., preferably about −10° C. to about 10° C., more preferably about 0° C.

[0057] Bases suitable for the generation of the anion of ester VIII are alkali metal hexaalkylsilylamides such as lithium hexamethylsilylamide or sodium hexamethylsilylamide, alkali metal dialkyl amides such as sodium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, preferably lithium diisopropyl amide.

[0058] Reaction temperatures vary from about −78° C. to about 25° C., preferred starting temperature is about −78° C., with the ending temperature about 25° C.

[0059] Suitable bases for treating fluoroester IX are metal hydrides such as sodium hydride and potassium hydride, alkali metal hexa-alkylsilylamide such as sodium hexamethylsilylamide or lithium hexamethysilylamide, alkali metal dialkylamides such as sodium diisopropylamide or lithium diisopropylamide, preferably lithium diisopropylamide.

[0060] Suitable bases for the formation of I are pyridine and substituted pyridines, preferably collidine. Reaction temperatures vary from about 25° C. to about 200° C., preferably from about 100° C. to about 200° C., more preferably from about 170° C. to about 180° C.

[0061] In actual practice, racemic ester II in water is treated with an esterase enzyme, preferably horse liver esterase, preferably between pH 7.1-8.0 to yield a first mixture of either R-acid IIIa and S-ester IIIb or S-acid IIIc and R-ester IIId; said acid can be separated from said ester by standard extraction techniques, preferably with aqueous sodium bicarbonate followed by acidification with mineral acid, preferably dilute hydrochloric acid and reextraction, or more preferably by chromatographic techniques, preferably on silica gel; said acid IIIa or IIIc is reduced with diborane, or said ester IIIb or IIId is reduced with diisobutylaluminum hydride to afford chiral alcohol IV having the R- or the S-configuration; said alcohol IV is reacted with at least one molar equivalent of a sulfonyl halide Ar₂SO₂Cl, preferably an arylsulfonyl chloride in a non-polar aprotic solvent, preferably methylene chloride, in the presence of at least one molar equivalent of a base, preferably a tertiary organic base, more preferably triethylamine to afford sulfonate V; said sulfonate V is reacted with a cyanide-delivering agent, preferably an alkali metal cyanide, more preferably sodium cyanide, in a polar aprotic solvent, preferably dimethylsulfoxide, to yield nitrile VI; nitrile VI is hydrolized in the presence of aqueous acid or base, preferably dilute aqueous sodium hydroxide followed by acidification of the resulting salt with strong mineral acid, preferably concentrated hydrochloric acid, to yield acid VII. Acid VII is esterified with an alcohol R₁OH, preferably present in excess, in the presence of a strong acid catalyst, preferably anhydrous hydrogen chloride gas, to yield ester VIII.

[0062] Said ester is fluorinated, preferably by generating its anion with a base, preferably an alkali metal amide, more preferably lithium diisopropyl amide in an aprotic solvent, preferably tetrahydrofuran, followed by quenching said anion with an electrophilic fluorinating agent, preferably an N-fluoroimide, more preferably N-fluorobenzenesulfonimide to yield fluoro ester IX; said fluoro ester IX is reacted with an aldehyde Ar₁CH₂CHO in the presence of a base, preferably an alkali metal amide, more preferably lithium diisopropylamide, in an aprotic solvent, preferably tetrahydrofuran, to afford a second mixture of 4 chiral diasteromeric hydroxy-esters of formula X; advantageously said second mixture X may be optionally separated, preferably by chromatographic techniques, more preferably on silica gel, into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers; said hydroxy-ester mixture X, Xa or Xb is treated with an acylating agent R₂COX₁, preferably an acid anhydride (R₂CO)₂O, more preferably acetic anhydride, in a non-polar solvent, preferably methylene chloride in the presence of an acylation catalyst, preferably N,N-dimethylaminopyridine, to afford a fifth mixture of 4 chiral diastereomeric acyloxy esters XI, a sixth mixture of 2 aryloxy esters of formula XIa, or a seventh mixture of 2 chiral diasteromeric acyloxy esters of formula XIb; advantageously said sixth or seventh mixture are optionally separated preferably by chromatographic techniques, more preferably with silica gel into essentially pure chiral diastereomeric acyloxy esters; said pure chiral acyloxy esters or mixtures of esters of formula XI are hydrolyzed with acid or base, preferably dilute aqueous metal hydroxide, more preferably dilute aqueous sodium hydroxide followed by acidification with a strong mineral acid, preferably concentrated hydrochloric acid, to afford a hydroxy-acid of formula XII; said hydroxy-acid is treated in the presence of an aryl-sulfonyl halide Ar₃SO₂X₂, preferably an arylsulfonyl chloride, more preferably p-toluene sulfonyl chloride, to afford the desired chiral compound of formula 1.

[0063] The present invention also provides chiral compounds of formula XIII

[0064] wherein

[0065] Ar is phenyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy or hydroxy groups,

[0066] 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or

[0067] a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups;

[0068] R is C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl or C₃-C₆halocycloalkyl;

[0069] Ar₁ is phenoxyphenyl optionally substituted with any combination of from one to six halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0070] phenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0071] biphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0072] phenoxypyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0073] benzylpyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0074] benzylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0075] benzoylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups,

[0076] 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or

[0077] a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, and

[0078] R₃ is H or C₁-C₄ alkyl; and

[0079] Z is H or COR₂, wherein R₂ is C₁-C₄ alkyl.

[0080] Preferred compounds of the present invention are those wherein

[0081] Ar is phenyl optionally substituted with any combination of from one to three halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups; and

[0082] R is C₁-C₄alkyl or C₃-C₆cycloalkyl.

[0083] More preferred compounds are those wherein

[0084] Ar₁ is phenyl optionally substituted with one to three halogen groups; and

[0085] R is C₃-C₆cycloalkyl.

[0086] Most preferred compounds are those selected from the group consisting of

[0087] methyl (2S,3S)-2[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0088] methyl (2R,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0089] methyl (2S,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0090] methyl (2R,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0091] methyl (2S,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0092] methyl (2R,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0093] methyl (2S,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0094] methyl (2R,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0095] methyl(2S,3S)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0096] methyl(2R,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0097] methyl(2R,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0098] methyl(2S,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0099] methyl(2S,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0100] methyl(2R,3R)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0101] methyl(2R,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0102] methyl(2S,3R)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate;

[0103] (2S,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid;

[0104] (2R,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid;

[0105] (2R,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid;

[0106] (2S,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid;

[0107] (2S,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid;

[0108] (2R,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid;

[0109] (2R,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid, and

[0110] (2S,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid.

[0111] The present invention additionally provides chiral compounds of formula XIV

[0112] wherein

[0113] Q is —CO₂H; —CO₂CH₃; —CH₂OH; —CH₂OSO₂Ar₂; —CH₂CN; —CH₂CO₂H; —CH₂CO₂R₁; or —CHFCO₂R₁;

[0114] Ar₂ is phenyl, p-chlorophenyl, or p-tolyl; and

[0115] R₁ i s C₁-C₄alkyl.

[0116] Most preferred compounds are selected from the group consisting of

[0117] (2R)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate;

[0118] (2S)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate;

[0119] (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile;

[0120] (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile;

[0121] (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid;

[0122] (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid;

[0123] methyl (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoate;

[0124] methyl (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoate;

[0125] methyl (3R)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate;

[0126] methyl(3S)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate;

[0127] In order to present a clear understanding of the invention, the following examples are set forth below. These examples are merely illustrative, and are not to be understood as limiting the scope and underlying principles of the invention in any way.

EXAMPLE 1 Preparation of (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic Acid and Methyl(2S)(4-chlorophenyl)(cyclopropyl)ethanoate

[0128]

[0129] Horse liver esterase (4.6 g horse liver acetone powder, Sigma Chemical Co.) is suspended in water (200 ml) at room temperature and the pH is adjusted to 7.5 with 1.0 M sodium hydroxide. Methyl (2RS)-(4-chlorophenyl)(cyclopropyl)ethanoate (7.0 g, 31.4 mol) is added and stirring is continued at room temperature with the addition of 1.0 M sodium hydroxide as needed to maintain the pH at 7.1-8.0. After 14 ml of base had been consumed, the pH was brought to 3 with 10% hydrochloric acid, ethyl acetate is added and the mixture is filtered through diatomaceous earth. The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography affords (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (2.5 g, 37.9%) and recovered ester (4.1 g). The ester was resubjected to the hydrolysis conditions with additional horse liver esterase (1.0 g ) for an extended period during which an additional 4.4 ml of 1.0 M sodium hydroxide is consumed. Acidification, workup and purification as described above affords methyl (2S)-(4-chlorophenyl)(cyclopropyl)ethanoate (3.1 g, 36.2%) The enantiomeric excess of (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (as the methyl ester) and (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid are determined with the chiral NMR shift reagent Eu(hfc)₃ to be >96:4 and >98:2 respectively.

EXAMPLE 2 Preparation of (2R)-2-(4-chlorophenyl)-2-cyclopropylethanol

[0130]

[0131] To a stirred solution of (2R)-(4-chlorophenyl)(cyclopropyl)ethanoic acid (7.25 g, 34.4 mmol) in tetrahydrofuran (200 ml) at 0° C. under nitrogen is added dropwise over one hour borane-tetrahydrofuran complex (58 ml of a 1.0 solution in tetrahydrofuran, 58 mmol). The solution is warmed to room temperature and stirred for an additional 4 h. The reaction mixture is cooled to 0° C. and carefully quenched by the dropwise addition of water: THF (1:1, 50 ml). The mixture is diluted with ethyl acetate (250 ml) and washed with water (250 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with ether:hexane (25:75 to 40:60) to afford the title compound as a colorless syrup (5.70 g, 84%) which is characterized by ¹HNMR, ¹³CNMR and mass spectral analyses.

EXAMPLE 3 Preparation of (2S)-2-(4-chlorophenyl)-2-cyclopropylethanol

[0132]

[0133] To a stirred solution of methyl(2S)-(4-chlorophenyl)(cyclopropyl)ethanoate (7.72 g, 34.4 mmol) in methylene chloride (300 ml) at −78° C. under nitrogen is added diisobutyl aluminum hydride (86 ml of a 1.0 M solution in methylene chloride, 86.0 mmol). The reaction mixture is allowed to warm to room temperature and stirred for an additional hour. The reaction is quenched by the addition of saturated aqueous ammonium chloride and then filtered. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (15:85) to afford the title compound as a colorless liquid (5.45 g, 80%) which is characterized by ¹HNMR, ¹³CNMR and mass spectral analyses.

EXAMPLE 4 Preparation of (2R)-2-(4-Chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate

[0134]

[0135] (2R)-2-(4-Chlorophenyl)-2-cyclopropylethanol (6.50 g, 33.0 mmol), tosyl chloride (7.86 g, 41.0 mmol) and 6.0 ml of triethylamine (6.0 ml) are dissolved in dichloromethane (150 ml) and allowed to stir for 3 days. The reaction mixture is washed successively with 1 N HCl (100 ml), water (100 ml) and saturated brine solution (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90 to 25:75) to afford the title compound as a colorless oil (11.1 g, 96%) which is characterized by ¹HNMR, ¹³CNMR and mass spectral analysis.

EXAMPLE 5 Preparation of (2S)-2-(4-Chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate

[0136]

[0137] Using the procedure of Example 4, (2S)-2-(4-chlorophenyl)-2-cyclopropylethanol yields the title compound as a colorless liquid which is characterized by ¹HNMR, IR and mass spectral analysis.

EXAMPLE 6 Preparation of (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile

[0138]

[0139] A mixture of (2R)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate (11.00 g, 31.3 mmol) and NaCN (4.62 g, 94.3 mmol) in dimethyl sulfoxide (100 ml) is heated at to 90° C. for 3 hours. The dimethyl sulfoxide was removed in vacuo and the resulting mixture is partitioned between water (200 ml) and diethyl ether (200 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue chromatographed on silica gel eluting with ether:hexane (25:75) to afford the title compound as a colorless oil (5.62 g, 87%) which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 7 Preparation of (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile

[0140]

[0141] Using the procedure of Example 6, (2S)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate yields the title compound as a colorless liquid which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 8 Preparation of (3R)-3-(4-Chlorophenyl)-3-cyclopropylpropanoic Acid

[0142]

[0143] (3R)-3-(4-Chlorophenyl)-3-cyclopropylpropanenitrile (5.30 g, 25.8 mmol) is refluxed for 18 hours in a mixture of methanol (100 ml) and a 10% aqueous sodium hydroxide (100 ml). Methanol is removed in vacuo, the residual solution is cooled to 0° C. and acidified to pH 4 with concentrated hydrochloric acid. The aqueous layer is extracted with ethyl acetate (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless liquid (5.79 g, 100%) which is characterized by ¹HNMR, IR and mass spectral analysis and used without further purification.

EXAMPLE 9 Preparation of (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoic Acid

[0144]

[0145] Using the procedure of Example 8, (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile yields the title compound as a colorless oil, which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 10 Preparation of Methyl(3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoate

[0146]

[0147] Hydrogen chloride gas is bubbled into a solution of (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid (5.79 g, 25.85 mmol) in methanol (100 ml) at 0° C. for 30 seconds. The solution is allowed to warm to room temperature and stirred for 18 hours. The solution is concentrated in vacuo, diluted with chloroform (100 ml) and washed with 5% aqueous sodium bicarbonate (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to yield the title compound as a colorless liquid (5.15 g, 84% from (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile) which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 11 Preparation of Methyl(3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoate

[0148]

[0149] Using the procedure of Example 10, (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid yields the title compound as a colorless liquid which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 12 Preparation of Methyl (3R)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate

[0150]

[0151] To a stirred solution of lithium diisopropyl amide (30 mmol) in dry tetrahydrofuran (125 ml) under nitrogen at −78° C. is added dropwise a solution of methyl(3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoate (6.5 g, 27.2 mmol) in dry tetrahydrofuran (50 ml). The reaction mixture is allowed to warm to 0° over 5 minutes, re-cooled to −78° C., and N-fluorobenzenesulfonimide (19.1 g, 60.6 mmol) is added.

[0152] The reaction is allowed to warm to room temperature, stirred an additional 2 hours, and then partitioned between ether (200 ml) and saturated ammonium chloride (200 ml). The solids are filtered off and the organic layer is separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to yield the title compound as a colorless liquid (6.40 g, 92%) which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 13 Preparation of Methyl(3S)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate

[0153]

[0154] Using the procedure of Example 12, methyl(3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoate yields the title compound as an off-white semi-solid which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 14 Preparation of 4-Fluoro-3-phenoxybenzaldehyde

[0155]

[0156] After dissolving sodium metal (0.41 g, 17.8 g-atom) in ethanol (25 ml), nitropropane (1.65 g) and 4-(bromomethyl)-1-fluoro-2-phenoxybenzene (5.00 g) are added and the mixture stirred for 3.5 h. The reaction was filtered and concentrated in vacuo. The residue is taken up in ether and washed with water (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to afford the title compound as a colorless liquid which is characterized by ¹HNMR spectral analyses.

EXAMPLE 15 Preparation of 1-Fluoro-4-[(E)-2-methoxyethenyl]-2-phenoxybenzene

[0157]

[0158] To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (2.48 g) in ether (50 ml) at room temperature under nitrogen is added phenyllithium (4 ml of a 1.8 M solution in ether, 7.2 mmol) and the resulting mixture stirred for 20 minutes. 4-fluoro-3-phenoxybenzaldehyde (1.30 g, 6.0 mmol) is then added and the reaction is stirred for 4 hours The reaction mixture was diluted with saturated aqueous ammonium chloride (20 ml) and diethyl ether (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (5:95) to afford the title compound as a colorless liquid (1.30 g, 89%) which is characterized by ¹HNMR, IR and mass spectral analyses.

EXAMPLE 16 Preparation of (4-Fluoro-3-phenoxyphenyl) acetaldehyde

[0159]

[0160] A mixture of 1-fluoro-4-[(E)-2-methoxyethenyl]-2-phenoxybenzene (0.50 g), concentrated hydrochloric acid (2 ml) and tetrahydrofuran (10 ml) is stirred at room temperature for 1 hour. The reaction is diluted with water (100 ml), the organic layer is separated and dried over anhydrous sodium sulfate, and the solvent is removed in vacuo to give the title compound as a colorless liquid (0.43 g, 41%) which is characterized by ¹HNMR, mass spectral analyses and used without further purification.

EXAMPLE 17 Preparation of Methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(SRR and (SRS or SSR)] and Methyl 2-[(4-chlorophenyl)(cyclopronyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyohenyl)-3-hydroxybutanoate [(SSS) and (SSR or SRS)]

[0161]

[0162] To a stirred solution of a lithium diisopropylamide in tetrahydrofuran (7.75 ml of 2M lithium diisopropylamide in tetrahydrofuran added to 50 ml of dry tetrahydrofuran) under nitrogen at −78° C. is added dropwise a solution of methyl(3S)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate (3.6 g, 11.9 mmol) in dry tetrahydrofuran, and the resulting mixture stirred for 15 minutes. A solution of (4-fluoro-3-phenoxyphenyl)acetaldehyde (3.23 g, 14.0 mmol) in dry tetrahydrofuran is then added dropwise and the resulting mixture is stirred for 2 hours at −78° C. The reaction is quenched at −78° C. with saturated aqueous ammonium chloride (2 ml) and partitioned between ether (50 ml) and water (50 ml). The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (25:75) to yield methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(SRR) and (SRS or SSR)] (1.17 g) as a colorless oil, and Methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(SSS) and (SSR or SRS)] (1.65 g) as a colorless oil, both of which are characterized by ¹HNMR and ¹⁹FNMR spectral analyses. The overall yield based on recovered starting materials is 50%.

EXAMPLE 18 Preparation of Methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(RSS) and (RSR) or (RRS)] and Methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-Phenoxyphenyl)-3-hydroxybutanoate [(RRR) and (RSR or RRS)]

[0163]

[0164] Using the procedure of Example 17, methyl(3R)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate yields the title compounds which are characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 19 Preparation of Methyl(2R,3R)-3-(acetyloxy)2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (SRR isomer) and methyl(2R,3S or 2S,3R)-3-(acetyloxy)2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (SRS or SSR isomer/Diastereomer A)

[0165]

[0166] A solution of methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(SRR) and (SRS or SSR)] (1.17 g, 2.40 mmol), acetic anhydride (1.50 ml) and dimethylaminopyridine (0.11 g) in methylene chloride is stirred for 2 hours at room temperature (30 ml). The solvent is removed in vacuo and the residue is chromatographed on silica gel eluting with ether:hexane (15:85) to afford methyl (2S,3S)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (0.20 g) and methyl(2R,3S or 2S,3R)-3-(acetyloxy)2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (SRS or SSR isomer/Diastereomer A) (0.80 g) as pure diastereomers in 79% overall yield and >98% ee as determined by ¹⁹FNMR spectral analysis.

EXAMPLE 20 Preparation of Methyl (2S,3S)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (SSS isomer) and methyl ((2R,3S or 2S,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (SRS or SSR isomer/Diastereomer B)

[0167]

[0168] Using the procedure of Example 19, methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate {(SSS) and (SRS or SSR)] affords the title compounds as pure diastereomers which are characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 21 Preparation of Methyl (2S,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-2-phenoxyphenyl)butanoate (RSS isomer) and Methyl (2S,3R or 2R,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-2-phenoxyphenyl)butanoate (RSR or RRS/Diastereomer C)

[0169]

[0170] Using the procedure of Example 19, methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(RSS) and (RSR or RRS)] yields the title compounds as pure diastereomers which are characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 22 Preparation of Methyl(2R,3R)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (R,R,R) and Methyl(2S,3R or 2R,3S)-3-(acetyloxy)-2-[(R)-(4-chloro-phenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (RSR or RRS/Diastereomer D)

[0171]

[0172] Using the procedure of Example 19, methyl 2-[(4-chlorophenyl)(cyclopropyl)methyl-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoate [(RRR) and (RSR or RRS)] yields the title compounds as pure diastereomers which are characterized by ¹HNMR and ¹⁹FNMR spectral analysis. The structure of methyl(2S,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate is also confirmed by x-ray crystal structure analysis.

EXAMPLE 23 Preparation of (2R, 3S or 2S,3R)-2-[(S)-(4chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro -3-phenoxyphenyl)-3-hydroxybutanoic acid (SRS or SRR/Diastereomer E)

[0173]

[0174] A mixture of methyl (2R,3S or 2S,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (Diastereomer B) (0.80 g, 1.50 mmol), aqueous sodium hydroxide (25 ml), methanol (20 ml) and tetrahydrofuran (5 ml) is refluxed for 1 hour. The organic solvents are removed in vacuo, the mixture is diluted with ethyl acetate and acidified to pH 3 with concentrated hydrochloric acid. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a colorless semi solid, which is characterized by ¹HNMR and ¹⁹FNMR and used without further purification.

EXAMPLE 24 Preparation of (2S,3R or 2R,3S)-2-[(S)-(4-chlorophenyl(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic Acid (Diastereomer F)

[0175]

[0176] Using the procedure of Example 23, methyl (2S,3R or 2R,3S)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl) (cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate (Diastereomer A) yields the title compound as a pure diastereomer which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 25 Preparation of (2S,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic Acid

[0177]

[0178] Using the procedure of Example 23, methyl (2S,3S)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate yields (2S,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid as a pure diastereomer which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 26 Preparation of (2R,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic Acid

[0179]

[0180] Using the procedure of Example 23, methyl (2R, 3R)-3-(acetyloxy) 2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate yields the title compound as a pure diastereomer which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 27 Preparation of (2R,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic Acid

[0181]

[0182] Using the procedure of Example 23, methyl(2R,3R)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate yields the title compound as a pure diastereomer which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 28 Preparation of (2S,3R or 2R,3S)-2-[(R)-(4-chlorophenyl) (cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic Acid

[0183]

[0184] Using the procedure of Example 23, methyl (2S, 3R or 2R, 3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl) (cyclopropyl)methyl]2-fluoro-4-(4-flouro-3-phenoxyphenyl)butanoate (Diastereomer D) yields the title compound as a pure diastereomer which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 29 Preparation of 4-[(2Z,4S)-4-(4-chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene

[0185]

[0186] A solution of crude (2R,3S or 2S,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid (Diastereomer E) (0.72 g, 1.5 mmol), tosyl chloride (0.58 g, 3.0 mmol) and collidine (20 ml) is heated at 170° C. for 2 hours. The mixture is concentrated in vacuo and the residue chromatographed on silica gel eluting with ether:hexane (5:95) to yield the title compound as a colorless liquid (0.43 g, 69% from diasteriomer B), [α]_(D)=+35.8 (C=0.0438, CHCl₃) which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 30 Preparation of 4-[(2Z,4S)-4-(4-Chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene

[0187]

[0188] Using the procedure of Example 29, (2S,3R or 2R,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid (Diastereomer F) yields the title compound as a colorless liquid which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 31 Preparation of 4-[(2E,4S)-4-(4-chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene

[0189]

[0190] Using the procedure of Example 29, (2S,3S)-2-[(S)(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid yields the title compound as a colorless liquid which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 32 Preparation of 4-[(2E,4S)-4-(4-chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene

[0191]

[0192] Using the procedure of Example 29, (2R,3R)-2-[(S)(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid yields the title compound as a colorless liquid which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 33 Preparation of 4-[(2E,4R)-4-(4-Chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene

[0193]

[0194] Using the procedure of Example 29, (2R,3R)-2-[(R)(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid yields the title compound as a colorless liquid which is characterized by ¹HNMR and ¹⁹FNMR spectral analyses.

EXAMPLE 34 Preparation of 4-[(2Z,4R)-4-(4-chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene

[0195]

[0196] Using the procedure of Example 29, (2S,3R or 2R,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid (Diastereomer G) yields 4-[(2Z,4R)-4-(4-chlorophenyl)-4-cyclopropyl-3-fluoro-2-butenyl]-1-fluoro-2-phenoxybenzene as a colorless oil which is characterized by ¹HNMR and ¹⁹FNMR spectral analysis. 

What is claimed is:
 1. A process for the preparation of a chiral compound of formula I

wherein Ar is phenyl optionally substituted with any combination of from one to three halogen, C₃-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy or hydroxy groups, 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups; R is C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl or C₃-C₆halocycloalkyl; Ar₁ is phenoxyphenyl optionally substituted with any combination of from one to six halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, phenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, biphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, phenoxypyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, benzylpyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, benzylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, benzoylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, 0₁-C₄alkoxy or C₁-C₄haloalkoxy groups, 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, and the (E)- and (Z)-isomers thereof, which process comprises the following steps: a) treating a racemic ester of formula II

wherein Ar and R are defined as hereinabove and R₄ is C₁-C₄alkyl with an esterase to form a first mixture of either R-acid IIIa and S-ester IIIb

or of S-acid IIIc and R-ester IIId

b) separating said acid IIIa or IIIc from said ester IIIb or IIId; c) reducing said acid IIIa or IIIc or said ester IIIb or IIId to obtain a chiral alcohol IV having the R- or S-configuration

d) reacting said chiral alcohol with an arylsulfonyl halide Ar₂SO₂X wherein Ar₂ is phenyl, p-chlorophenyl, or p-tolyl, and X is chloro, bromo or fluoro to afford a sulfonate of formula V

e) reacting said sulfonate V with a cyanide-delivering agent to afford a nitrile of formula VI

f) hydrolyzing said nitrile VI to afford an acid of formula VII

g) esterifying said acid VII with an alcohol R₁OH, wherein R, is C₁-C₄ alkyl to afford an ester of formula VIII

h) fluorinating said ester to afford a fluoro-ester of formula IX

i) reacting said fluoro ester with an aldehyde Ar₁CH₂CHO, wherein Ar₁ is defined as hereinabove, in a solvent in the presence of a base to afford a second mixture of 4 chiral diastereomeric hydroxy-esters of formula X;

j) optionally separating said second mixture X into a third mixture Xa and a forth mixture Xb, each mixture having two chiral diastereomers; k) treating said hydroxy-ester mixture X, Xa or Xb with an acylating agent R₂COX₁, wherein R₂ is C₁-C₄alkyl and X₁ is Cl, Br or R₂COO, to afford a fifth mixture of 4 chiral diastereomeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or a seventh mixture of 2 chiral diastereomeric acyloxy esters XIb

l) optionally separating said sixth or seventh mixture into essentially pure chiral diastereomeric acyloxy esters; m) hydrolyzing said pure chiral acyloxy esters or mixtures of esters of formula XI to afford a hydroxy-acid of formula XII,

and n) heating said hydroxy-acid XII with an arylsulfonyl halide Ar₃SO₂X₂, wherein Ar₃ is phenyl, p-chlorophenyl, or p-tolyl, and X₂ is chloro or bromo to afford the desired chiral compound of formula I.
 2. The process according to claim 1 wherein said esterase is horse liver esterase.
 3. The process according to claim 1 wherein said base is lithium diisopropylamide.
 4. The process according to claim 1 wherein said solvent is tetrahydrofuran.
 5. The process according to claim 1 wherein R₄ is methyl.
 6. A chiral compound of the following formula

wherein Ar is phenyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy or hydroxy groups, 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups; R is C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl or C₃-C₆halocycloalkyl; Ar₁ is phenoxyphenyl optionally substituted with any combination of from one to six halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, phenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, biphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, phenoxypyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, benzylpyridyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, benzylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, benzoylphenyl optionally substituted with any combination of from one to five halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, 1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, or a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups, and R₃ is H or C₁-C₄ alkyl; and Z is H or COR₂, wherein R₂ is C₁-C₄ alkyl.
 7. The compound according to claim 6 wherein Ar is phenyl optionally substituted with any combination of from one to three halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy groups; and R is C₁-C₄alkyl or C₃-C₆cycloalkyl.
 8. The compound according to claim 7 wherein Ar₁ is phenyl optionally substituted with one to three halogen groups; and R is C₃-C₆cycloalkyl.
 9. The compound according to claim 8 selected from the group consisting of methyl (2S,3S)-2[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2R,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2S,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2R,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2S,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2R,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2S,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl (2R,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2S,3S)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2R,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2R,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2S,3R)-3-(acetyloxy)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2S,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2R,3R)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2R,3S)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; methyl(2S,3R)-3-(acetyloxy)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)butanoate; (2S,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; (2R,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; (2R,3S)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; (2S,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; (2S,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; (2R,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; (2R,3S)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid; and (2S,3R)-2-[(R)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid.
 10. A chiral compound of the following formula

wherein Q is —CO₂H; —CO₂CH₃; —CH₂OH; —CH₂OSO₂Ar₂; —CH₂CN; —CH₂CO₂H; —CH₂CO₂R₁; or —CHFCO₂R₁; Ar₂ is phenyl, p-chlorophenyl or p-tolyl; and R₁ is C₁-C₄alkyl.
 11. The compound according to claim 10 selected from the group consisting of (2R)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate; (2S)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate; (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile; (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile; (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid; (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid; methyl (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoate; methyl (3S)-3-(4-chlorophenyl)-3-cyclopropylpropanoate; methyl (3R)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate; and methyl(3S)-3-(4-chlorophenyl)-3-cyclopropyl-2-fluoropropanoate. 